The importance of an economically viable synthesis of single-enantiomer chiral molecules is well established and understood. In no sector is this more apparent than in the pharmaceutical industry, where one enantiomer of a chiral drug molecule may exhibit enhanced (or different) therapeutic properties over another enantiomer.
While in many cases chiral resolution often remains the method of choice for large scale production, asymmetric hydrogenation remains the most widespread catalytic alternative because of the economic and environmental benefits over older resolution technologies in which the unwanted enantiomer must be recycled or disposed of.
However, despite the inherent advantages in using asymmetric catalysis to produce single-enantiomer molecules, the process is not readily amenable to use at an industrial scale because of a number of factors: such as the ready availability of the chiral catalyst for public or licensed use in the required quantity at an affordable price, the presence of impurities in the catalyst, which can either inhibit the effectiveness of the catalyst itself or get carried into the final product where they are difficult to remove and that, there is no single ligand family, much less an individual member of a family, which leads to high enantiomer selectivity with all substrates.
Moreover, no general methodology exists, although stereoselective asymmetric hydrogenation reductions of various substrates have been extensively described (Ohta T, Miyake T, Seido N, Kumabayashi H and Takaya H, J. Org. Chem. 1995, 60, 357; Dobbs D A, Vanhessche K P M, Brazi E, Rautenstrauch V, Lenoir J-Y, Genet J-P, Wiles J, and Bergens S H, Angew. Chem., Int. Ed. Engl. 2000, 39, 1992; Menges F and Pfaltz A, Adv. Synth. Catal. 2002, 344, 40; Tang W and Zhang X, Chem. Rev. 2003, 103, 3029; Ohta T, Takaya H, Kitamura M, Nagai K and Noyori R, J. Org. Chem. 1987, 52, 3174; Liqin Q, Li Y.-M, Kwong F Y, Yu W-Y, Fan Q-H and Chan A S C, Adv. Synth. Catal. 2007, 349, 517; Hayashi T, Kawamura N and Ito Y, J. Am. Chem. Soc. 1987, 109, 7876; Uemura T, Zhang X, Matsumura K, Sayo N, Kumobayashi H, Ohta T, Nozaki K and Takaya H, J. Org. Chem. 1996, 61, 5510; Tellers D M, McWilliams J C, Humphrey G, Journet M, DiMichele L, Hinksmon J, McKeown A E, Rosner T, Sun Y, and Tillyer R D, J. Am. Chem. Soc. 2006, 128, 17063; Cossy J and Belotti D, Biorg. Med. Chem. Lett 2001, 11, 1989; Blaser H U, Malan C, Pugin B, Steiner H, Spindler F and Studer M, Adv. Synth. Catal. A 2003, 345, 103 and references therein; Romero D L, Manninen P R, Han F and Romero A G, J. Org. Chem. 1999, 64, 4980-4985; U.S. Pat. No. 6,465,664; and, U.S. Pat. No. 6,787,655.
There remains a need for an efficient enantiomerically and diastereomerically selective hydrogenation process for a chiral integrin antagonist with a maximum conversion to product, having the highest enantiomeric and diastereomeric excess of the desired isomer.